Three main projects are ongoing:
1. Cellular and molecular targets of Hedgehog signaling
The goal of this project is to learn more about the constant signaling crosstalk between intestinal epithelium and mesenchyme that acts to pattern the intestine. In earlier studies, we demonstrated that Indian and Sonic Hedgehog, secreted from the intestinal epithelium, are required for patterning both the mesenchyme and the epithelium itself. Mesenchymal patterning is due to a direct paracrine hedghog signal. Events downstream of hedgehog signals include the localization of Wnt-secreting myofibroblasts beneath the pre-crypt regions of the intestine, the generation of smooth muscle structures in the cores of the villi and control of the stromal inflammatory milieu. Epithelial patterning downstream of hedgehog signals is indirect and is controlled by secondary signals secreted from the mesenchyme, including Wnt, and Bmp. We have identified seven cell types in the intestinal mesenchyme that receive hedgehog signals. We are currently studying the molecular events downstream of those signals, including control of intestinal inflammation (relevant to inflammatory bowel disease) and generation of smooth muscle (relevant to intestinal obstruction and irritable bowel syndrome). We are also using new bioinformatic tools developed in our laboratory to identify cell-specific hedgehog signaling enhancers in genomic DNA. Work is ongoing to study the function and evolution of these hedgehog enhancers.
2. Patterning of the epithelial pyloric border
Using microarray approaches, we have discovered several genes that are uniquely expressed at the pylorus, the region connecting the stomach to the intestine. We have studied the effects of loss of function of one of these pyloric-specific genes, Gata3. We find that Gata3 is required for the generation of specific fascicles of smooth muscle at the pylorus. Additionally, Gata3 is required for the development of novel cord-like structures that may function as ligaments that either sense or control pyloric opening. Genetic mouse models are combined with ex vivo stomach/intestinal culture systems and live cell imaging in this project.
3. Organogenesis and patterning of the gastrointestinal tract
The intestinal surface contains millions of finger-like projections called villi that serve to increase the surface area for absorption. Loss of intestinal surface as in congenital anomalies such as short bowel syndrome or after surgical resection of bowel, is a life-threatening condition. We are studying how the embryonic intestine is remodeled to form the villi. The initial intestine is a thick pseudostratified epithelium; this becomes remodeled via dramatic changes in cell shape, in part driven by the Shroom protein family. Using genetic tools, we are studying the role of Shroom in cell shape change in the intestinal epithelium of the mouse embryo. Additionally, we have found that the formation of villi resembles in many ways the formation of hair or feather follicles, in that mesenchymal condensates form signaling centers that "talk" to the epithelium and dictate its cell shape changes. We have found that these mesenchymal clusters are themselves under the control of hedgehog and PDGF signals; indeed, loss of hedgehog signaling prevents cluster formation and villus emergence. These studies utilize high resolution live cell imaging, 3D reconstructions, mouse models and ex vivo intestinal cultures.

Li X, Madison BB, Zacharias W, Kolterud A, States D, Gumucio DL.
Deconvoluting the intestine: molecular evidence for a major role of the mesenchyme in the modulation of signaling cross talk.
Physiol Genomics. 2007 May 11;29(3):290-301.

1986 Distinguished Dissertation Award, Rackham School of Graduate Studies, University of Michigan
2001 Faculty Career Development Award, Office of the Provost, University of Michigan
2005 Sheldon Wolff Award in Translational Research from the International Congress on Systemic Autoinflammatory Diseases
2004 to present: Associate Editor, Molecular and Cellular Biology
2007 NIH-NICHD Mentor Award for Excellence in Research Training